Posts Tagged ‘anderson-cancer’

Novel immunotherapy vaccine decreases recurrence in HER2 positive breast cancer patients

One of only a few vaccines of its kind in development, GP2 has been shown to be safe and effective for breast cancer patients, reducing recurrence rates by 57%. Further, women with the highest overexpression of HER2 (known as HER2 +3) had no cancer recurrences when they were administered the vaccine after completing trastuzumab (Herceptin), a type of immunotherapy drug known as a monoclonal antibody. HER2 is an oncoprotein that promotes tumor growth and is expressed to some extent in 75-80% of breast cancers.

“This is an important and different avenue in immunotherapy research, in that we are investigating ways to prevent cancer recurrence by stimulating the immune system to treat cancer,” says principal investigator Elizabeth Mittendorf, M.D., Ph.D., associate professor of Surgical Oncology. “The ultimate goal is to develop a preventative tool that will minimize the risk of recurrence in women who have already had breast cancer and for whom standard therapies have failed.”

The findings are the result of a phase II randomized trial that paired the GP2 vaccine, designed to stimulate the CD8+ cells, commonly known as “killer” or “toxic” T cells, with an immune stimulant known as granulocyte/macrophage colony stimulating factor (GM-CSF). The trial included 190 patients with varying levels of HER2; 89 women received the GP2 vaccine with a GM-CSF adjuvant and a control group of 91 patients received GM-CSF alone. Eight patients experienced early recurrence or developed a second malignancy and did not complete the vaccine trial. The vaccine is injected subcutaneously and the initial series consisted of monthly inoculations for six months, followed by four cycles of booster shots administered every six months thereafter. The patients were monitored for nearly three years.

For all 190 patients, including those who did not complete the trial, the disease-free survival (DFS) rate was 88% among those who received the vaccine and 81% in the control group — representing a 37% reduction in recurrence. Excluding the patients who did not complete the vaccine series, the results are higher — 94% DFS rate versus 85% who did not get GP2 — a 57% risk reduction.

Women with HER2 +3 who were administered trastuzumab as part of the standard of care prior to receiving the vaccine experienced no cases of cancer recurrence. According to Mittendorf, trastuzumab may act like a primer for the vaccine. Trastuzumab stimulates CD4+ T cells to release substances that fight cancer cells and initiates an antibody response. Thus, it may prepare the immune system, making the vaccine even more effective. MD Anderson is now testing this combination of immunotherapies in other clinical trials.

Personalized Immunotherapy

The GP2 study supports previous MD Anderson research on similar breast cancer vaccines, such as AE37, which showed a significant immune response and improved recurrence rates in triple-negative breast cancer patients. Another candidate, E75, known as NeuVax or nelipepimut-S, showed a 50% recurrence decrease in high-risk patients. Currently, NeuVax is being tested internationally in a phase III clinical trial.

“We believe many more patients will benefit in some way from immunotherapy,” says Mittendorf. “The challenge will be identifying the right immunotherapeutic approach for each individual patient. When doctors are able to do that, cancer therapy, and immunotherapy specifically, will follow a more personalized approach.”

source : http://www.sciencedaily.com/releases/2014/09/140905122717.htm

Protein ZEB1 promotes breast tumor resistance to radiation therapy

One protein with the even more out-there name of ZEB1 (zinc finger E-box binding homeobox 1), is now thought to keep breast cancer cells from being successfully treated with radiation therapy, according to a study at The University of Texas MD Anderson Cancer Center in Houston.

Li Ma, Ph.D., an assistant professor of experimental radiation oncology at MD Anderson, reported in this month’s issue of Nature Cell Biology that ZEB1 may actually be helping breast tumor cells repair DNA damage caused by radiation treatment by ramping up a first-line of defense known as DNA damage response pathway.

“Radiation therapy causes cell death by inducing DNA ‘ breaks’,” said Ma. “The rationale for treating tumors with radiation without damaging normal tissues is that, compared with normal cells, tumor cells are actively dividing and often have defects in DNA damage repair machinery.”

Tumor cells are thus less able to repair DNA damage. But not always. Sometimes the body produces tumor cells resistant to radiation. They are somehow able to “turn on” the DNA damage response apparatus. Until now, the question has always been how?

Ma’s team has demonstrated that the wily tumor cell’s ability to push the panic button at the last second can be triggered by ZEB1’s penchant for launching an operation that generates cancer stem cells.

“The cancer stem cells have been shown to promote radioresistance through activation of the DNA damage response system,” said Ma. “Our studies have shown that ZEB1 can induce a process known as epithelial-mesenchymal transition (EMT) which allows certain tumor to acquire cancer stem cell properties including radioresistance.”

EMT is one way the body responds to wound healing and it is believed that cancer has found a method for using EMT to promote tumor progression.

ZEB1 achieves this unfortunate result through a complex chain of events that permit a gene known as ATM to stabilize the protein Chk1 that plays an important role in DNA damage response. ZEB1 promotes Chk1’s ability to allow tumor radioresistance through deployment of an enzyme called USP7.

The hope is that new approaches to addressing radiation resistance may be developed through gaining better insight into how this signaling pathway keeps tumor cells growing despite being bombarded with toxic radiation treatments.

“Radiation therapy plays a key role in breast cancer management,” said Ma. “To overcome the obstacle of radioresistant tumor cells, it is important to identify the critical causes and to develop safe and effective new methods for treatment including the possible use of agents that target ZEB1 and which inhibit CHK1.”

source : http://www.sciencedaily.com/releases/2014/08/140804102940.htm

Cancer-promoting protein is vital to safe division of tumor cells

In a paper published in Molecular Cell, Zhimin Lu, Ph.D., professor of Neuro-Oncology at The University of Texas MD Anderson Cancer Center and colleagues report how a tumor-specific protein flips a crucial switch in an irregular mechanism for mitosis that allows cancer cells to safely divide.

"Our research shows that tumor cells rely heavily on a distinct mechanism for orderly cell division that’s driven by oncogene-induced pyruvate kinase M2," Lu said. After a cell begins division by replicating all of its chromosomes, mitosis separates them into two identical sets of chromosomes for both cells. After mitosis, cytokinesis completes cell divison.

"Without PKM2 regulating a checkpoint in mitosis, the tumor cell would not successfully divide," Lu said. "Depleting PKM2 led to an uneven distribution of DNA to the two new cells, triggering programmed cell death, or apoptosis, of those cells after division."

"This new, additional role for PKM2 in cancer development and survival may provide a molecular basis for diagnosing and treating tumors with upregulated PKM2," Lu said. He and his colleagues have now identified four specific mechanisms by which PKM2 promotes cancer development.

PKM2 regulation of mitosis worsens tumors in mice; affects human glioblastoma

The key relationship between PKM2 activity and mitosis uncovered by the researchers led to rapid brain tumor growth when activated in mice, while blocking it reduced tumor volume by 83 percent and more than doubled survival from about 20 days to beyond 40 days.

Analysis of 50 human glioblastoma multiforme tumors and 50 lung cancer tumors confirmed the relationship in human cancer and indicated an effect on survival for patients with glioblastoma, the most common and lethal form of brain tumor.

PKM2 can act as a protein kinase, which gives orders to other proteins by attaching phosphate groups to them. While it plays a normal role in sugar metabolism, PKM2 also actively promotes cell growth during infancy when such growth is desired.

Usually, Lu said, it eventually turns off, but tumor cells reactivate PKM2, and it is famously overexpressed in solid tumors. This tumor-specific PKM2 is activated by the epidermal growth factor receptor (EGFR), which is overactive in a variety of cancers.

Deplete PKM2 in mitosis, tumor cells abnormally divide in multiple cancer types

A series of experiments in glioblastoma cell lines revealed that PKM2 phosphorylates a protein called Bub3, activating it to interact with others in a protein complex that assures orderly and equal chromosome separation. Depleting PKM2 blocked Bub3 activation, leading to an increase in cells with abnormal numbers of chromosomes and programmed cell death.

The team confirmed its findings in human breast, prostate, lung, pancreatic and colon cancer cell lines.

PKM2-induced Bub3 activation was essential for development of brain tumors in mice. Experiments in the 50 glioblastoma and lung cancer tumors confirmed that phosphorylation of Bub3 correlates with phosphorylation of H3-S10, a marker of cell mitosis in tumor cells.

With low Bub3 phosphorylation, glioblastoma patients live longer

Among the 50 glioblastoma patients, the 15 with low levels of Bub3 phosphorylation had a median survival of 69.8 weeks, compared to 40.5 weeks for the 35 patients with high levels of Bub3 activation.

Previous research by Lu and colleagues showed PKM2, usually active outside the cell nucleus, slips into the nucleus where it promotes cancer formation, growth and survival by:

• Activating an important transcription co-factor that, in turn, activates other cancer-promoting genes.

• Phosphorylating the histone protein H3, loosening the packaging of DNA and leading to the activation of cell division genes.

• Inducing expression of glycolytic genes (including PKM2 itself) and triggering a glucose metabolism mechanism called the Warburg effect that nourishes tumor cells.

Potential avenues for thwarting these effects identified in their experiments include two classes of drug that inhibit SRC and MEK activity.

"Our research further highlights the importance of PKM2 in human cancers and of developing ways to target its activity and use it as a biomarker to guide treatment," Lu said.

source : http://www.sciencedaily.com/releases/2013/12/131206162957.htm